PROJECT SUMMARY Candidate: Daniel Machin, PhD is a postdoctoral fellow in the Translational Physiology Laboratory at the University of Utah. Dr. Machin?s research is focused on the impact of high molecular weight hyaluronan (HMW- HA) dietary supplementation on the vascular and skeletal muscle function in advanced age. Dr. Machin?s long- term goal is to independently direct an extramurally funded laboratory with research focused on natural countermeasures to aging and age-related diseases. Career Development: This award will support Dr. Machin?s career development by building on his existing training in aging cardiovascular and exercise physiology. Specifically, Dr. Machin will receive extensive training in the planning and execution of studies assessing skeletal muscle mitochondrial function and hemodynamics in rodents. The career development plan outlines a coordinated effort to train the candidate in areas including: vascular biology of aging; assessment of skeletal muscle mitochondrial respiration, blood flow distribution, and microvascular oxygen perfusion; didactic course work designed to facilitate a better understanding of fundamentals of therapeutic product development, animal research, and biostatistics; and, regular attendance at vascular aging, nutrition, microcirculatory, and exercise physiology conferences. Environment: The University of Utah is an ideal environment for Dr. Machin?s career development. This environment provides all of the resources needed to complete the proposed studies during the K99 phase and allows for collaboration with experts in aging, vascular biology, and exercise physiology. The University of Utah also provides a rich environment for formal and informal training in career development. Research: The central hypothesis of this research project is that age-related reductions in HMW-HA result in a deteriorated glycocalyx that leads to micro/macrovascular dysfunction that impairs skeletal muscle hemodynamics, attenuating maximal exercise capacity. Furthermore, we hypothesize that chronic HMW-HA dietary supplementation can reverse age-related glycocalyx deterioration and micro/macrovascular dysfunction, as well as prevent the decline in maximal exercise capacity with advanced age. To test these hypotheses we will assess glycocalyx thickness, micro/macrovascular function, maximal exercise capacity, and skeletal muscle hemodynamics and mitochondrial function in young and old mice, as well as in inducible, endothelial HMW-HA synthase 2 (HAS2) knockout and control mice. To determine if there are any direct effects of HMW-HA on skeletal muscle, we will also assess exercise and skeletal muscle outcomes in inducible, skeletal muscle HAS2 knockout and control mice. The results from these studies will provide insight into the etiology of age-related vascular and skeletal muscle dysfunction and provide a proof of mechanism of action for HMW-HA in prevention of age-related diseases.